Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells (46.45)

Abstract

Abstract Tumor angiogenesis plays an important role in the development and progression of solid tumors. Targeting the tumor vasculature has emerged as a strategy to prevent growth and progression of solid tumors. In this study, we showed that murine tumor vasculature express Rae1, a ligand for a stimulatory natural killer receptor NKG2D. By genetic modification of T cells with a chimeric NKG2D receptor (chNKG2D), in which the NKG2D receptor is fused to the signaling domain of CD3ζ chain, we generated T cells that are capable of targeting tumor vasculature, leading to reduced tumor angiogenesis as well as tumor growth in tumors where the tumor cells do not express NKG2D ligands themselves. H5V, an endothelial cell line, expresses Rae1 and can be lysed by chNKG2D-bearing T cells in a perforin-dependent manner. In vitro capillary tube formation by H5V was inhibited by both soluble factors (IFN-γ) and cell-cell contact by chNKG2D T cells. The in vivo anti-tumor angiogenesis efficacy mediated by chNKG2D T cells was also dependent on IFN-γ and perforin. In addition, chNKG2D T cells could inhibit VEGF expression by myeloid derived suppressor cells (MDSCs). In summary, these results provide a novel mechanism for NKG2D-targeting of solid tumors.